tbuckley/cabot-search huggingface dataset:
Abstract 479: Novel specific PKM2 inhibitor, compound 3h, induces apoptotic and autophagic cell death through Akt/mTOR signaling pathway in prostate cancer cells
Authors: Chunxue Jiang, Tian Zheng, HwaYoung Cha, Hyung Sik Kim
Journal: Cancer Research (2023)

Abstract Pyruvate kinase M2 (PKM2) is a key enzyme involved in the regulation of glycolysis. Although PKM2 is overexpressed in various tumor tissues, its functional role in cancer chemotherapy remains unclear. In this study, we investigated the anticancer activity of novel PKM2 inhibitors in the regulation of cell metabolism and its associated pathways in prostate cancer cells. To evaluate the molecular basis of specific PKM2 inhibitors, the interactions of compounds 3h and 3K with the PKM2 protein were assessed via molecular docking. We found that, compared to compound 3K, compound 3h exhibited a higher binding affinity for PKM2. Moreover, compound 3h significantly inhibited the pyruvate kinase activity and PKM2 expression. Cytotoxicity and colony formation assays revealed the potent anticancer activity of compound 3h against LNCaP cells. Compound 3h significantly increased the apoptotic and autophagic cell death in LNCaP cells. In addition, compound 3h induced AMPK activation along with the inhibition of mTOR/p70S6K pathway. Furthermore, compound 3h significantly inhibited glycolysis and mitochondrial respiration, as determined by analyzing extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) production. Our results revealed that compound 3h caused apoptotic and autophagic cell death by inhibiting cancer cell metabolism in LNCaP cells. Therefore, blocking glycolytic pathways using specific PKM2 inhibitors can be used to target cancer cell metabolism in PKM2-overexpressed prostate cancer cells. Citation Format: Chunxue Jiang, Tian Zheng, HwaYoung Cha, Hyung Sik Kim. Novel specific PKM2 inhibitor, compound 3h, induces apoptotic and autophagic cell death through Akt/mTOR signaling pathway in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 479.
Abstract 4786: Imipridones induce lipid peroxidation and oxidative stress in gastrointestinal malignancies
Authors: Arielle De La Cruz, Praveen R. Srinivasan, Andrew George, Varun V. Prabhu, Maximilian P. Pinho-Schwermann, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract Colorectal and pancreatic cancer collectively comprise 20% of all cancer-related deaths in the United States. Despite therapeutic advancements, the current standard of care often results in significant toxicity. Therefore, there is an urgent need to develop more efficacious novel therapies. The imipridones, ONC201/TIC10, ONC206, and ONC212, are novel small-molecules that bind mitochondrial ClpP and induce activation of the integrated stress response (ISR), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling, and oxidative stress. Each has previously demonstrated antitumor effects in a variety of preclinical in vitro and in vivo cancer subtypes, including colorectal cancer, with limited toxicity. Reactive oxidation species (ROS) are natural biproducts of cellular oxidative metabolism and play important roles in the modulation of cell death pathways, differentiation, and immune response. Using varying doses of ONC201, ONC206, and ONC212, we observed increased lipid peroxidation in several colorectal and pancreatic cancer cell lines using the C-11 BODIPY assay which measures lipid-specific peroxides. Lipid peroxidation was reversed by the ferroptosis inhibitor liproxstatin-1, suggesting that in addition to inducing apoptosis, imipridones may be involved in ferroptosis induction. Future directions include mechanistic work, investigation of the effect of imipridone-induced lipid peroxidation on immune cell cytotoxicity, and understanding the relative importance of lipid peroxidation in the clinical efficacy of imipridones. Citation Format: Arielle De La Cruz, Praveen R. Srinivasan, Andrew George, Varun V. Prabhu, Maximilian P. Pinho-Schwermann, Wafik S. El-Deiry. Imipridones induce lipid peroxidation and oxidative stress in gastrointestinal malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4786.
Abstract 4472: A mouse model for GvHD: an excellent tool for evaluating the efficacy of anti-GvHD drugs and testing mechanisms of immunoregulation
Authors: Meirong Wu, Shiru Zhang, Fang Zhu, Hongyan Sun, Jianming Xu, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao
Journal: Cancer Research (2023)

Abstract Hematological malignancies, including leukemia, lymphoma and multiple myeloma, account for about 7% of all newly diagnosed cancers. Allogeneic hematopoietic stem cell transplantation (HSCT) is a traditional treatment for hematologic malignancies. Currently, CAR-T cell therapy has made a major breakthrough in the treatment of hematologic malignancies. However, the occurrence of acute Graft-versus-Host Disease (GvHD) represents a major obstacle for HSCT and limits the application of CAR-T cell therapy. GemPharmatech established and characterized two murine models for anti-GvHD drug evaluation. In the first model, bone marrow from C57BL/6 donor mice was transplanted into a sublethally-irradiated BALB/c recipient mouse. In this model, T cell infiltration, tissue damage, and systemic inflammation were observed, similar to the clinical observations of patients receiving allogeneic HSCT. Efficacy evaluation of anti-GVHD drugs have been carried out based on this model. Our results showed that treatment with the anti-GVHD drug Ibrutinib, the survival rate and the lifespan of the mice was significantly prolonged, and the GvHD score was reduced by about 70% compared with the placebo group. In the second model, human Peripheral Blood Mononuclear cells (PBMCs) were transplanted into irradiated severe immunodeficient NCG mice. The cohort was irradiated to accelerate GvHD occurrence. The reconstructed human T cells will recognize and attack mouse tissues to cause GvHD. Our results showed that hCD45+ cells infiltrated into heart, liver, and spleen of huPBMC-NCG mice. This model has also been successfully used for anti-GvHD efficacy evaluation. Upon treatment with an anti-GVHD drug, the lifespan of huPBMC-NCG mice was significantly extended and weight loss was alleviated. Overall, the above-mentioned GvHD models show great potential for preclinical evaluation of anti-GvHD drug development in allogeneic HSCT. Citation Format: Meirong Wu, Shiru Zhang, Fang Zhu, Hongyan Sun, Jianming Xu, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. A mouse model for GvHD: an excellent tool for evaluating the efficacy of anti-GvHD drugs and testing mechanisms of immunoregulation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4472.
Abstract 4807: BACH1 proline hydroxylation regulates the hypoxia response and metastasis in triple negative breast cancer
Authors: Long Chi Nguyen, Christopher Dann, Dongbo Yang, Emily Shi, Thomas Li, Joseph Wynne, Letícia Stock, Madeline Henn, Zeyu Qiao, Andrea Valdespino, Raven Watson, Wenchao Liu, Lydia Robinson-Mailman, Galina Khramtsova, Mitsuyo Matsumoto, Raymond Moellering, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Marsha R. Rosner
Journal: Cancer Research (2023)

Abstract Hypoxia is an important hallmark of aggressive solid tumors. Here we show that the pro-metastatic BTB and CNC homology 1 (BACH1) transcription factor is prolyl-hydroxylated by the HIF Prolyl Hydroxylase 1 (PHD1) in an oxygen-dependent manner. Using mass spectrometry, we identified two major prolyl hydroxylation sites in BACH1 and demonstrate that prolyl hydroxylation increased protein turnover in normoxia. Notably, a clinically relevant BACH1 mutant (BACH1M) resistant to hydroxylation displays enhanced BACH1 DNA binding capacity. Triple-negative breast cancer (TNBC) cells expressing BACH1M showed higher invasion in vitro and increased metastasis in vivo. Loss of BACH1 reduced the cellular transcriptional hypoxic response. Under hypoxia, BACH1 increases chromatin accessibility and gene expression through chromatin remodeling involving direct BACH1 binding and indirect epigenetic regulation. These results indicate that hypoxia stabilizes and enhances the pro-metastatic transcriptional activity of BACH1 through loss of prolyl hydoxylation in TNBC. Our findings identify BACH1 as an oxygen sensitive effector of the hypoxia response and a clinically relevant target for attenuating hypoxia induced, pro-metastatic signaling and therapeutic resistance in cancers. Citation Format: Long Chi Nguyen, Christopher Dann, Dongbo Yang, Emily Shi, Thomas Li, Joseph Wynne, Letícia Stock, Madeline Henn, Zeyu Qiao, Andrea Valdespino, Raven Watson, Wenchao Liu, Lydia Robinson-Mailman, Galina Khramtsova, Mitsuyo Matsumoto, Raymond Moellering, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Marsha R. Rosner. BACH1 proline hydroxylation regulates the hypoxia response and metastasis in triple negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4807.
Abstract 4781: New generation of fluorescent probes for cell-based measurements of caspase activation and mitochondrial superoxide
Authors: Bhaskar S. Mandavilli, Daniel Beacham, Yi Zhen Hu, Jongtae Yang, Aimei Chen
Journal: Cancer Research (2023)

Abstract Cell health and stress readouts are critical indicators of altered or impaired function in normal and diseased states of cells, and work has been underway to develop improved small molecule sensor dyes compatible with traditional imaging and High Content Analysis (HCA) interrogation of apoptotic and mitochondrial stress pathways. The CellEvent™ Caspase Green dye effectively reports caspase activation, but suffers complications in assay configuration when attempting to multiplex with the Green Fluorescent Protein (GFP), calcein, or other 488 laser line tools in fluorescence microscopy. Here, we describe the testing and functional characterization of a new candidate molecule for measuring apoptosis in living cells. Our sensor is comprised of a fluorogenic reporter dye that is liberated from a DEVD peptide substrate by caspase activation, but operates in the Texas Red, 590nm excitation band, with an emission peak near 610 nm, permitting easy multiplex with GFP or calcein stained neurons in both traditional and HCA microscopy configurations. Similarly, mitochondrial superoxide accompanying cell stress is probed in microscopy with the MitoSOX™ Red Mitochondrial Superoxide Indicator dye, which localizes to mitochondria and reports superoxide generation, ignoring other Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS). This dye has an unusually long Stokes’ shift, requiring specialized microscopy and HCA filters that excite at 405nm, and capture emission at 610nm for specific superoxide detection. This unconventional spectroscopic profile prevents the dye’s use on many imaging platforms and promotes phototoxicity. To this end, our team has produced a dye with the same level of specificity for superoxide that will operate in one of the traditional fluorescence microscopy channels. Our candidate dye, here named MitoSOX™ Green Mitochondrial Superoxide Indicator also localizes to mitochondria of live cells and selectively reports superoxide generation, while ignoring other ROS and RNS species in ex vivo testing. With an Excitation/Emission profile in the GFP/FITC microscopy channel, a series of comparative studies in immortalized and neural cells are shown, highlighting photostability, specificity and signal amplitude from the dye. These reagents are research use only, not for diagnostic purposes Citation Format: Bhaskar S. Mandavilli, Daniel Beacham, Yi Zhen Hu, Jongtae Yang, Aimei Chen. New generation of fluorescent probes for cell-based measurements of caspase activation and mitochondrial superoxide. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4781.
Abstract 4787: The cancer targeting synergy of tertbutylhydroquinone and a manganese porphyrin
Authors: Joseph P. LaMorte, Sandra Tamarin, Margueritte Lalo, David J. Sokoloski, Jared J. Paul, Aimee L. Eggler
Journal: Cancer Research (2023)

Abstract Cancer cells utilize high basal levels of reactive oxygen species (ROS) to create conditions that facilitate rapid cell proliferation. This creates an Achilles heel, making cancer cells more susceptible than normal cells to cell death caused by a bolus dose of ROS. The common food preservative, tert-butylhydroquinone (tBHQ), generates ROS intracellularly via redox cycling. Herein, we tested the effect of combining tBHQ with a manganese porphyrin, compounds originally designed as super oxide dismutase mimetics which can also generate ROS intracellularly in cancer cells and have radioprotective effects under clinical investigation. We find that the combination treatment of tBHQ and the commercially available Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP) is much more toxic to leukemic Jurkat lymphocytes than either compound alone, e.g., lowering the LC50 of tBHQ by two orders of magnitude to 1.0 μM. MnTMPyP acts as a catalyst to oxidize tBHQ, shown by UV-Vis spectroscopy. Flow cytometry analysis revealed that while 5 μM tBHQ decreases cell viability by less than 10% in 4 hours, the combination of 5 μM tBHQ and 12 μM MnTMPyP decreases viability by 60%, primarily by apoptosis. A clinically tested manganese porphyrin, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (Mn2BuOE), was as effective and more potent than MnTMPyP. We evaluated the cancer-targeting effect of tBHQ and Mn2BuOE in both Jurkats and a matched primary CD4 T cell line. The combination treatment induced significantly more cell death in cancerous Jurkats than in the normal CD4 cells. With the promise Mn2BuOE shows in pre-clinical studies and early clinical trials as adjunctive to radiotherapy, and the wide use of tBHQ in prepared food, the results shown here in CD4 cells suggest their combination may be an effective therapy to target cancer cells. Citation Format: Joseph P. LaMorte, Sandra Tamarin, Margueritte Lalo, David J. Sokoloski, Jared J. Paul, Aimee L. Eggler. The cancer targeting synergy of tertbutylhydroquinone and a manganese porphyrin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4787.
Abstract 4808: Hypoxic HIF-1α stabilization dependent on β3-adrenoceptor localization in Ewing sarcoma
Authors: Amada Pasha, Claudia Masi, Francesco Carrozzo, Martina Rosati, Alessia Boaretto, Alessandro Pini, Claudio Favre, Maura Calvani
Journal: Cancer Research (2023)

Abstract Hypoxia is a condition of oxygen deficiency which occurs in most growing solid tumors and stimulates a cascade of cell signals through a family of transcription factors named as hypoxia inducible factors (HIFs) that transactivate several regulatory genes involved in tumor proliferation. β3-adrenoceptors (β3-ARs) are involved in several hypoxic scenarios and in pathological conditions where hypoxia leads to important steps for cancer progression. Studies showed that β-AR blockade of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. In this work we assumed that β3-AR mediates hypoxia sensing and that it was necessary for HIF-1α stabilization thus we investigated a putative correlation between β3-AR/HIF-1α. Data showed a similar outcome of β3-ARs and HIF-1α at short time of hypoxia, and that β3-AR antagonist, SR59230A reduced HIF-1α protein expression under hypoxia. β3-AR silencing under hypoxia revealed an evident reduction of HIF-1α protein expression that confirmed the β3-AR modulation of HIF-1α expression. SR59230A treatment strongly reduced the HIF-1α target genes as GLUT1, HK-2 and HIF-1α expression at long time treatment confirming the β3-AR modulation of HIF-1α transcriptional activity. Conversely, the HIF-1α-transcriptional inhibitor Topotecan did not affect β3-AR expression confirming that is β3-AR that mediates HIF-1α activation. Immunofluorescence analysis showed that β3-AR co-localized with the nucleus under hypoxia more than normoxia. These results were confirmed by nuclear-cytoplasmic fragmentation that showed the presence of both β3-AR and HIF-1α proteins in the nucleus under hypoxia. Co-immunoprecipitation of β3-AR/HIF-1α revealed that under hypoxia, HIF-1α dissociates from β3-AR binding, but this process was abrogated by SR59230A. HIF-1α, released under hypoxia from the link with β3-AR, can play its transcriptional activity in the nucleus, while the binding with β3-AR blocks its transcriptional activity. Moreover, β3-AR regulation on HIF-1α was exerted through PHD2 activity at short time as SR59230A treatment under hypoxia increased the PHD2 protein expression but not at long time treatment, thus showing a different regulation of HIF-1α at different time points. In conclusion, the β3-AR upstream of the signaling β3-AR/HIF-1α axis exerts its role by PHD2 activity. Citation Format: Amada Pasha, Claudia Masi, Francesco Carrozzo, Martina Rosati, Alessia Boaretto, Alessandro Pini, Claudio Favre, Maura Calvani. Hypoxic HIF-1α stabilization dependent on β3-adrenoceptor localization in Ewing sarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4808.
Abstract 5421: Constructing the largest-scale knowledge graph using all PubMed abstracts and its application for highly specific and accurate knowledge retrieval
Authors: Xin Sui, Yuan Zhang, Feng Pan, Donghu Sun, Menghan Chung, Jinfeng Zhang
Journal: Cancer Research (2023)

Abstract Most of the biomedical knowledge the research community has acquired during the past few decades has been deposited in scientific literature as unstructured text. Converting the unstructured text into the structured form will enable novel methodologies and applications for scientific discovery that can fully harness the power of the existing knowledge. To this end, two fundamental questions need to be addressed: named entity recognition (NER) and relation extraction (RE). NER deals with identifying the concepts or entities in texts, such as diseases, genes/proteins, chemical compounds, etc. while RE aims to extract the relations among these entities. Together, the extracted information forms a knowledge graph (KG) where the nodes are entities in the texts and the edges represent their relationships. KGs can link concepts within existing research to allow researchers to find connections that may have been difficult to discover without them. The LitCoin Natural Language Processing (NLP) Challenge was recently organized by NCATS of NIH and NASA to spur innovation by rewarding the most creative and high-impact uses of biomedical text to create KGs. Our team participated in the challenge and ranked first place. We have applied the methods we developed for the LitCoin NLP challenge to all PubMed abstracts and constructed the largest-scale biomedical KG to date. We show that powerful and versatile query functions can be implemented on top of the KG to enable highly specific and accurate knowledge retrieval and inference of causal and indirect relationships. Citation Format: Xin Sui, Yuan Zhang, Feng Pan, Donghu Sun, Menghan Chung, Jinfeng Zhang. Constructing the largest-scale knowledge graph using all PubMed abstracts and its application for highly specific and accurate knowledge retrieval. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5421.
Abstract 5428: Skeletal muscle gauge prediction by a machine learning model in patients with colorectal cancer
Authors: Jeonghyun Kang
Journal: Cancer Research (2023)

Abstract Background: Skeletal muscle gauge (SMG) was recently introduced as an imaging indicator of sarcopenia for the prediction of clinical outcomes, including chemotherapy toxicity and prognosis, in patients with cancer. Computed tomography (CT) is essential for measuring SMG; thus, the use of SMG is limited to patients who undergo CT. Objective: We aimed to develop a machine learning algorithm using clinical and inflammatory markers to predict SMG in patients with colorectal cancer (CRC) Methods: The least absolute shrinkage and selection operator (LASSO) regression model was applied for variable selection and predictive signature building in the training set. The predictive accuracy of the LASSO model, defined as LP-SMG was compared using the area under the receiver operating characteristic (AUROC) and decision curve analysis (DCA) in the test set. Results: A total of 1,094 patients with CRC were enrolled and randomly categorized into training (n=656) and test (n=438) sets. Low SMG was identified in 142 (21.6%) and 90 (20.5%) patients in the training and test sets, respectively. According to multivariable analysis of the test sets, LP-SMG was identified as an independent predictor of low SMG (OR: 1329.431, CI: 271.684-7667.996, p&amp;lt;.001). Its predictive performance was similar in the training and test sets (AUROC: 0.846 vs. 0.869, p=.427). In the test set, LP-SMG showed better outcomes in predicting SMG than single clinical variables, such as sex, height, weight, and hemoglobin, as measured by AUROC and DCA. Conclusions: LP-SMG, incorporating clinical variables and serum inflammatory indicators, showed superior performance compared to single variables in predicting low SMG. This machine learning model can be used as a screening tool to detect sarcopenic status without using CT during the treatment period. Applying a machine learning model might be beneficial in reducing the effort, cost, and radiation exposure from conventional CT-based diagnosis. Citation Format: Jeonghyun Kang. Skeletal muscle gauge prediction by a machine learning model in patients with colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5428.